| First Author | Inoshima I | Year | 2011 |
| Journal | Nat Med | Volume | 17 |
| Issue | 10 | Pages | 1310-4 |
| PubMed ID | 21926978 | Mgi Jnum | J:177286 |
| Mgi Id | MGI:5294700 | Doi | 10.1038/nm.2451 |
| Citation | Inoshima I, et al. (2011) A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat Med 17(10):1310-4 |
| abstractText | Staphylococcus aureus is a major cause of human disease, responsible for half a million infections and approximately 20,000 deaths per year in the United States alone. This pathogen secretes alpha-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia. alpha-hemolysin injures epithelial cells in vitro by interacting with its receptor, the zinc-dependent metalloprotease ADAM10 (ref. 6). We show here that mice harboring a conditional disruption of the Adam10 gene in lung epithelium are resistant to lethal pneumonia. Investigation of the molecular mechanism of toxin-receptor function revealed that alpha-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin. Cleavage is associated with disruption of epithelial barrier function, contributing to the pathogenesis of lethal acute lung injury. A metalloprotease inhibitor of ADAM10 prevents E-cadherin cleavage in response to Hla; similarly, toxin-dependent E-cadherin proteolysis and barrier disruption is attenuated in ADAM10-knockout mice. Together, these data attest to the function of ADAM10 as the cellular receptor for alpha-hemolysin. The observation that alpha-hemolysin can usurp the metalloprotease activity of its receptor reveals a previously unknown mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury and defines ADAM10 inhibition as a strategy to attenuate alpha-hemolysin-induced disease. |
